Tadashi Goto

Radiofrequency Ablation for Hepatocellular Carcinoma: 10-Year Outcome and Prognostic Factors

OBJECTIVES:Radiofrequency ablation (RFA) is widely performed for hepatocellular carcinoma (HCC). However, there has been no report on 10-year outcome of RFA. The objective of this study was to report a 10-year consecutive case series at a tertiary referral center.METHODS:We performed 2,982 RFA treatments on 1,170 primary HCC patients and analyzed a collected database.RESULTS:Final computed tomography images showed complete tumor ablation in 2,964 (99.4%) of 2,982 treatments performed for the 1,170 primary HCC patients. With a median follow-up of 38.2 months, 5- and 10-year survival rates were 60.2% (95% confidence interval (CI): 56.7–63.9%) and 27.3% (95% CI: 21.5–34.7%), respectively. Multivariate analysis demonstrated that age, antibody to hepatitis C virus (anti-HCV), Child-Pugh class, tumor size, tumor number, serum des-γ-carboxy-prothrombin (DCP) level, and serum lectin-reactive α-fetoprotein level (AFP-L3) were significantly related to survival. Five- and 10-year local tumor progression rates were both 3.2% (95% CI: 2.1–4.3%). Serum DCP level alone was significantly related to local tumor progression. Five- and 10-year distant recurrence rates were 74.8% (95% CI: 71.8–77.8%) and 80.8% (95% CI: 77.4–84.3%), respectively. Anti-HCV, Child-Pugh class, platelet count, tumor size, tumor number, serum AFP level, and serum DCP level were significantly related to distant recurrence. There were 67 complications (2.2%) and 1 death (0.03%).CONCLUSIONS:RFA could be locally curative for HCC, resulting in survival for as long as 10 years, and was a safe procedure. RFA might be a first-line treatment for selected patients with early-stage HCC.

The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance

After receiving lamivudine for 3 years to treat chronic hepatitis B, 67-75% of patients develop B-domain L528M, C-domain M552I, or M552V mutations in the HBV polymerase that render hepatitis B virus (HBV) drug-resistant. The aim of this study was to evaluate the influence of these mutations on viral replication and resistance to antiviral agents. We investigated the replication fitness and susceptibility of the wild-type and five mutant HBVs (L528M, M552I, M552V, L528M/M552I, and L528M/M552V) to 11 compounds [lamivudine, adefovir, entecavir (BMS-200475) (+)-BCH-189 (+/-)-FTC (racivir) (-)-FTC (emtricitabine) (+)-FTC, L-D4FC, L-FMAU (clevudine), D-DAPD, and (-)-carbovir] by transfecting HBV DNA into hepatoma cells and monitoring viral products by Southern blotting. The replication competency of the single C-domain mutants M552I and M552V was markedly decreased compared with that of wild-type HBV. However, addition of the B-domain mutation L528M restored replication competence. Only adefovir and entecavir were effective against all five HBV mutants, and higher doses of these compounds were necessary to inhibit the double mutants compared with the single mutants. The B-domain mutation (L528M) of HBV polymerase not only restores the replication competence of C-domain mutants, but also increases resistance to nucleoside analogues.

Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography

Liver stiffness, noninvasively measured by transient elastography, correlates well with liver fibrosis stage. The aim of this prospective study was to evaluate the liver stiffness measurement (LSM) as a predictor of hepatocellular carcinoma (HCC) development among patients with chronic hepatitis C. Between December 2004 and June 2005, a total of 984 HCV‐RNA positive patients, without HCC or a past history of it, visited the University of Tokyo Hospital. LSM was performed successfully in 866 patients, who gave informed consent. During the follow‐up period (mean, 3.0 years), HCC developed in 77 patients (2.9% per 1 person‐year). The cumulative incidence rates of HCC at 1, 2, and 3 years were 2.4%, 6.0%, and 8.9%, respectively. Adjusting for other significant factors for HCC development, patients with higher LSM were revealed to be at a significantly higher risk, with a hazard ratio, as compared to LSM ≤10 kPa, of 16.7 (95% confidence interval [CI], 3.71‐75.2; P < 0.001) when LSM 10.1‐15 kPa, 20.9 (95% CI, 4.43‐98.8; P < 0.001) when LSM 15.1‐20 kPa, 25.6 (95%CI, 5.21‐126.1; P < 0.001) when LSM 20.1‐25 kPa, and 45.5 (95% CI, 9.75‐212.3; P < 0.001) when LSM >25 kPa. Conclusions: This prospective study has shown the association between LSM and the risk of HCC development in patients with hepatitis C. The utility of LSM is not limited to a surrogate for liver biopsy but can be applied as an indicator of the wide range of the risk of HCC development. (HEPATOLOGY 2009.)

Hepatocellular carcinoma with extrahepatic metastasis: clinical features and prognostic factors.

Despite significant advances in the treatment of intrahepatic lesions, the prognosis for patients with hepatocellular carcinoma (HCC) who have extrahepatic metastasis remains poor. The objective of this study was to further elucidate the clinical course and prognostic determinants of patients with this disease.

Hepatitis C Virus Core Protein Enhances p53 Function through Augmentation of DNA Binding Affinity and Transcriptional Ability

Hepatitis C virus (HCV) causes a persistent infection, chronic hepatitis, and hepatocellular carcinoma. Since there are several reports indicating that some viruses influence the tumor suppressor p53 function, we determined the effects of HCV proteins on p53 function and its mechanism determined by use of a reporter assay. Among seven HCV proteins investigated (core, NS2, NS3, NS4A, NS4B, NS5A, and NS5B), only core protein augmented the transcriptional activity of p53 and increased the expression of p21 waf1 protein, which is a major target of p53. Core protein increased both DNA-binding affinity of p53 in electrophoretic morbidity shift assay and transcriptional ability of p53 itself in a reporter assay. The direct interaction between core protein and C terminus of p53 was also shown by glutathioneS-transferase fusion protein binding assay. In addition, core protein interacted with hTAFII28, a component of the transcriptional factor complex in vivo and in vitro. These results suggest that HCV core protein interacts with p53 and modulates p53-dependent promoter activities during HCV infection.

Obesity Is an Independent Risk Factor for Hepatocellular Carcinoma Development in Chronic Hepatitis C Patients

BACKGROUND & AIMS It is not fully elucidated whether obesity enhances hepatocarcinogenesis in patients with chronic hepatitis C. The aim of this study was to investigate the relationship between body weight and risk of hepatocarcinogenesis in chronic hepatitis C patients. METHODS We enrolled 1431 patients with chronic hepatitis C who visited our liver clinic between 1994 and 2004, excluding those with hepatocellular carcinoma (HCC) at their visit or with a previous history of HCC. They were divided into 4 groups according to body mass index (BMI): underweight (< or =18.5 kg/m(2), N = 112); normal (18.5 to less than 25 kg/m(2), N = 1023); overweight (25 to less than 30 kg/m(2), N = 265); and obese (>30 kg/m(2), N = 31). We assessed the impact of obesity on the hepatocarcinogenesis adjusted by multivariate Cox proportional hazard regression with other risk factors found significant in univariate analysis. RESULTS During the follow-up period (mean, 6.1 y), HCC developed in 340 patients, showing cumulative incidence rates of 10.5%, 19.7%, and 36.8% at 3, 5, and 10 years, respectively. The incidence differed significantly among the BMI groups (P = .007). Adjusting for other significant factors, overweight and obesity were shown to be an independent risk factor of HCC, with a hazard ratio of 1.86 (95% confidence interval, 1.09-3.16; P = .022) and 3.10 (95% confidence interval, 1.41-6.81; P = .005) as compared with the underweight patients. CONCLUSIONS The risk of HCC in patients with chronic hepatitis C increases in proportion to BMI in a wide range of its values, from underweight to obese.

Visceral fat accumulation is an independent risk factor for hepatocellular carcinoma recurrence after curative treatment in patients with suspected NASH

Background and Aim: Visceral fat accumulation reportedly increases the risk of hepatocellular carcinoma (HCC) development in patients with chronic liver disease. However, it has not beeen fully elucidated whether visceral fat accumulation increases the risk of HCC recurrence after curative treatment in patients with suspected non-alcoholic steatohepatitis (NASH). Therefore this was investigated in the current study. Methods: 62 patients with naïve HCC with suspected NASH were enrolled. All were curatively treated with percutaneous radiofrequency ablation between 1999 and 2006. The visceral fat area (VFA) was determined in each patient from CT images, taken at the time of HCC diagnosis. Patients were divided into two groups based on VFA: the high VFA group (>130 cm2 in males, >90 cm2 in females, n = 27) and the others (n = 35). The effects of VFA on HCC recurrence were analysed together with other factors including patients’ background, tumour-related factors and liver function-related factors. Results: The cumulative recurrence rates differed significantly between the two groups; 15.9, 56.5 and 75.1% at 1, 2 and 3 years, respectively, in the high VFA group, and 9.7, 31.1 and 43.1%, respectively, in the controls (p = 0.018). Multivariate analysis indicated visceral fat accumulation (risk ratio 1.08, per 10 cm2, p = 0.046) and older age (risk ratio 1.06 per 1 year, p = 0.04) as independent risk factors of HCC recurrence. Conclusions: Visceral fat accumulation is an independent risk factor of HCC recurrence after curative treatment in patients with suspected NASH.

Neoplastic seeding after radiofrequency ablation for hepatocellular carcinoma.

BACKGROUND:Neoplastic seeding reportedly occurs in up to 12.5% of patients treated with radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). The aim of this study is to assess the incidence, risk factors, and prognosis of neoplastic seeding after RFA among a large number of patients with a long-term follow-up.METHOD:From February 1999 to December 2004, 1,031 patients underwent a total of 1,845 treatments with RFA for a total of 3,837 HCC nodules. The following variables were assessed to elucidate the risk factors of neoplastic seeding: age, sex, positivity for viral markers, tumor size, number of tumor nodules, number of RFA sessions, tumor location, percutaneous biopsy prior to RFA, alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP) and lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) levels, and the degree of tumor differentiation.RESULTS:Neoplastic seeding was detected in 33 patients (3.2% per patient) at intervals of 4.8–63.8 (median, 15.2) months after RFA. On multivariate logistic regression analysis, only the poor differentiation degree was associated with the risk of neoplastic seeding (P = 0.012). Of tumor factors, tumor size, and AFP, DCP, and AFP-L3 levels were significantly associated with the poor differentiation degree. The cumulative survival rates 1 and 2 yr after the detection of neoplastic seeding were 86% and 47%, respectively.CONCLUSION:Poor differentiation degree was the risk factor of neoplastic seeding after RFA for HCC. The surrogate markers for poor differentiation degree were larger tumor size and elevated tumor marker levels. Indication for RFA should be carefully considered for HCC patients under these conditions.

Extrahepatic metastasis of hepatocellular carcinoma: incidence and risk factors

Background: Extrahepatic metastasis of hepatocellular carcinoma (HCC) is of growing importance as the survival of patients has been improved owing to advances in treatments to intrahepatic lesions.

MicroRNA‐140 acts as a liver tumor suppressor by controlling NF‐κB activity by directly targeting DNA methyltransferase 1 (Dnmt1) expression

MicroRNAs (miRNAs) are small RNAs that regulate the expression of specific target genes. While deregulated miRNA expression levels have been detected in many tumors, whether miRNA functional impairment is also involved in carcinogenesis remains unknown. We investigated whether deregulation of miRNA machinery components and subsequent functional impairment of miRNAs are involved in hepatocarcinogenesis. Among miRNA‐containing ribonucleoprotein complex components, reduced expression of DDX20 was frequently observed in human hepatocellular carcinomas, in which enhanced nuclear factor‐κB (NF‐κB) activity is believed to be closely linked to carcinogenesis. Because DDX20 normally suppresses NF‐κB activity by preferentially regulating the function of the NF‐κB‐suppressing miRNA‐140, we hypothesized that impairment of miRNA‐140 function may be involved in hepatocarcinogenesis. DNA methyltransferase 1 (Dnmt1) was identified as a direct target of miRNA‐140, and increased Dnmt1 expression in DDX20‐deficient cells hypermethylated the promoters of metallothionein genes, resulting in decreased metallothionein expression leading to enhanced NF‐κB activity. MiRNA‐140‐knockout mice were prone to hepatocarcinogenesis and had a phenotype similar to that of DDX20 deficiency, suggesting that miRNA‐140 plays a central role in DDX20 deficiency‐related pathogenesis. Conclusion: These results indicate that miRNA‐140 acts as a liver tumor suppressor, and that impairment of miRNA‐140 function due to a deficiency of DDX20, a miRNA machinery component, could lead to hepatocarcinogenesis. (HEPATOLOGY 2013)